1. Field of the Invention
The present invention is directed 6H-pyrrolo[3,4-d]pyridazine compounds and method of their use. In particular, this invention is directed to a method of use of 6H-pyrrolo[3,4-d]pyridazine compounds in the treatment of neuropathic pain.
2. Related Background
A major mechanism in many physiological processes, including neurotransmission in the mammalian nervous system, is the opening and closing of voltage gated calcium channels (“VGCC”), also known as voltage sensitive calcium channels (“VSCC”). Such VGCC are formed by the assembly of subunit classes such as alpha 1 and alpha 2. One subunit in the alpha 2 class is the α2δ subunit. The activity of the calcium channel can be modulated by the activities of the component subunits. For example, gabapentin is known to bind with high affinity to the α2δ subunit. Four isoforms of this α2δ protein are known and gabapentin binds with high affinity to 2 of these (α2δ-1 and α2δ-2). The relative importance of these two activities in accounting for the efficacy and adverse effects of gabapentin is not known. Compounds that display high-affinity binding to the α2δ subunit of voltage gated calcium channels have been shown to be efficacious for the treatment of, for example, neuropathic pain. See, J. Biol. Chem., 271(10):5768-5776(1996) and J. Med. Chem., 41:1838-1845(1998). Nonetheless, if one isoform is more controlling of the channel modulation, while the other is less, then compounds that are selective to the controlling isoform are likely to be more efficacious and display fewer side-effects.
Thus, it is desirable to identify other compounds that display high-affinity binding to the α2δ subunit of voltage gated calcium channels to provide new medicines in the treatment of neuropathic pain. Further, such compounds can be useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders—such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, drug withdrawal and other diseases.
International Patent Publication No. WO 01/88101describes a cell line for the expression of an α2δ2 calcium channel subunit.
6-Methyl-6H-pyrrolo[3,4-d]pyridazine is described in MM. J. Duflos et al., Tetrahedron Lett., 3453-3454(1973). 1,4,5,7-tetramethyl-6-phenyl-6H -pyrrolo [3,4-d]pyridazine, 1,4,5-trimethyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, 5,7-dimethyl-1,4,6-triphenyl-6H-pyrrolo[3,4-d]pyridazine, 5-methyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4-bis-(4-methoxy-phenyl)-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4-bis-(4-methoxy-phenyl)-5-methyl-6,7-diphenyl-6H-pyrrolo[3,4-d]pyridazine, and 1,4-diethyl-5,7-dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine are described in R. Rips et al., J. Org. Chem., 24:551-554(1959). 1,4,5,7-Tetramethyl-6H-pyrrolo[3,4-d]pyridazine, N-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-benzamide, 1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine picrate, and 1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-ylamine are described in W. L. Mosby, J. Chem. Soc., 3997-4003(1957). 5,7-Dimethyl-6-phenyl-6H-pyrrolo[3,4-d]pyridazine is described in R. Rips et al., J. Org. Chem., 24:372-374(1959).
5,7-Dimethyl-2-phenacyl-6H-pyrrolo[3,4-d]pyridazinium bromide (also known as 5,7-dimethyl-2-(2-oxo-2-phenyl-ethyl)-6H-pyrrolo[3,4-d]pyridazin-2-ium bromide) and 2-(2-methoxycarbonylvinyl)-5,7-dimethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafloroborate are described in F. Fuentes-Rodriguez et al., J. Chem. Res. Miniprint, 11:2901-2914(1987). 5,7-Diphenyl-6H-pyrrolo[3,4-d]pyridazine is described in T. Hernandez et al., J. Chem. Soc., Perkins Trans., 1:899-902(1985), and F. F. Rodriguez et al., J. Chem. Res. Miniprint, 11:3001-3001(1987). 5,6,7-Trimethyl-6H-pyrrolo[3,4-d]pyridazine is described in T. Hernandez et al., J. Chem. Soc., Perkin Trans., 1:899-902(1985), F. Fuentes-Rodriguez et al., J. Chem. Res. Miniprint, 11:2901-2914(1987), and R. von Kreher et al., Agnew Chem., 82:958(1970).
1,4-Diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine (also known as 1,4-diphenyl-5,6,7,8-tetrahydro-2,3,8a-triaza-fluorene) and 5-methyl-1,4-diphenyl-7,8,9,10-tetrahydro-pyridazino[4,5-a]indolizine (also known as 9-methyl-1,4-diphenyl-5,6,7,8-tetrahydro-2,3,8a-triaza-fluorene) are described in T. Uchida et al., J. Heterocycl. Chem., 15:1303-1307(1978). 6-Benzyl-1,4-diphenyl-5-p-tolyl-6, H-pyrrolo[3,4-d]pyridazine 6-benzyl-5-(2-chloro-phenyl)-1,4-diphenyl-6H-pyrrolo[3,4-d]pyridazine, 1,4,5,6,7-pentaphenyl-6H-pyrrolo[3,4-d]pyridazine,6,7,10,11-tetraphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoxaline (also known as 6,7,10,11-tetraphenyl-5,8,9,11a-tetraaza-benzo[a]fluorene), 11-(4-nitro-phenyl)-6,7,10-triphenyl-pyridazino[4′.5′:3,4]pyrrolo[1,2-a]quinoxaline (also known as 11-(4-nitro-phenyl)6,7,10-triphenyl-5,8,9,11a-tetraaza-benzo[a]fluorene), and 6-benzyl-1,4,5-triphenyl-6H-pyrrolo[3,4-d]pyridazine are described in T. Uchida et al., J. Heterocycl. Chem., 15:241-248(1978).
9,12-Diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline, 5-methylsulfanyl-1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine, and 1,4,6,7-tetraphenyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester are described in K. T. Potts et al., J. Org. Chem., 42:1639-1644(1977). 7,10-Diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-a]quinoline, and 11,14-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[1,2-f]phenanthridine (also known as 9,12-diphenyl-10,11,13a-triaza-indeno[1,2-l]phenanthrene) are described in K. T. Potts et al., J. Org. Chem., 44:977-979(1979).
1-Oxo-7-oxy-6b,11b-dihydro(pyridazino[4′,5′-c]-pyrrolo)[2,1-c]benzoxazine-1,4 (also known as 11-hydroxy-5-oxa-8,9,11a-triaza-benzo[a]fluoren-6-one) is described in Kumashiro et al., Nippon Kagaku Zasshi., 82:1072-1074(1961). 10-Methyl-1,4-diphenyl-8,9-dihydro-7H-benzo(ef)pyridazino[4,5-a]cycl[3.3.2]azine, and 11-methyl-1,4-diphenyl-7,8,9,10-tetrahydrocyclohepta(ef)pyridazino[4,5-a]cycl[3.3.2]azine are described in M. Noguchi et al., J. Heterocycl. Chem., 22:1049-1053(1985).
1,4-Dichloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, 1-chloro-4ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine, 1-chloro-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium chloride, 1-ethoxy-2,5,6,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate, 1-ethoxy-5,6,7-trimethyl-2H,6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate, 1-ethoxy-3-ethyl-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazinium tetrafluoroborate,and 1-ethoxy-5,6,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine are described in S. Inel et al., Tetrahedron, 40:3979-3986(1984).
5-Cyano-1,4-dimethylpyridazino[4,5-a]indolizine (also known as 1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile), 1,4-dimethyl-6-phenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzolyl-1,4-dimethyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and 1,4,6-trimethyl-2,3,8a-triaza-fluorene-9-carbonitrile are described in K. Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988). 5-Cyano-1,4-diphenylpyridazino[4,5-a]indolizine (also known as 1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile) is described in K. Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988), and K. Matsumoto et al., Heterocycles, 20:1525-1529(1983). 6-Methyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, 6-benzoyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and 1,4,6-triphenyl-2,3,8a-triaza-fluorene-9-carbonitrile are described in K. Matsumoto et al., J. Heterocycl. Chem., 25:1793-1801(1988), K. Matsumoto et al., Heterocycles, 34:2239-2242(1992), K. Matsumoto et al., Heterocycles, 20:1525-1529(1983), and K. Matsumoto et al., Can. J. Chem., 71:529-533(1993). 5,7-Dimethyl-1,4-diphenyl-2,3,8a-triaza-fluorene-9-carbonitrile, and 9,12-diphenyl-pyridazino[4′,5′:3,4]pyrrolo[2,1-a]isoquinoline-8-carbonitrile are described in K. Matsumoto et al., Heterocycles, 34:2239-2242(1992), and K. Matsumoto et al., Can. J. Chem., 71:529-533(1993).
Dimethyl 3,12,13,17-tetramethyl-72,73-diazabenzo[g]porphyrin-2,18-dipropionate is described in I. A. Chaudhry et al., Aust. J. Chem., 35:1185-11201(1982).5,6-Dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol, 5,6-dihydro-2,3-dimethoxypyridazino[4′,5′:3,4]pyrrolo[2,1-a]isochinolin-9-ol-hydrochloride, and 3-methyl-6,9-diphenylthiazolo[3′,2′:1,2]pyrrolo[3,4-d]pyridine (also known as 1-methyl-4,7-diphenyl-3-thia-5,6,8a-triaza-cyclopenta[a]indene) are described in W. Losel et al., Chem. Ber., 118:413-427 (1985). 1,4-Diphenylpyridazino[4′,5′:3,4]pyrrolo[2,1-b]benzothiazole (also known as 1,4-diphenyl-5-thia-2,3,9b-triaza-indeno[2,1-a]indene) is described in N. Abe et al., Bull. Chem. Soc. Japan, 55:200-203(1982).
Nevertheless, there is a need to identify 6H-pyrrolo[3,4-d]pyridazine compounds that display high-affinity binding—particularly selective binding—to the α2δ subunit of voltage gated calcium channels to provide new medicines in the treatment of neuropathic pain, as well as psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, bipolar disorders, and panic, as well as in the treatment of pain, Parkinson's disease, cognitive dysfunction, epilepsy, circadian rhythm and sleep disorders—such as shift-work induced sleep disorder and jet-lag, drug addiction, drug abuse, drug withdrawal and other diseases.